Scientists Find Non-Viral Pathway of Blood Cancer Development

Researchers reveal three new variations in the letters of the DNA code that give an increased risk of developing Hodgkin lymphoma. Two of these genetic variants are more common in people not exposed to the Epstein-Barr virus.

An international team of scientists led by The Institute of Cancer Research (ICR) has found three new regions of DNA linked to the development of Hodgkin lymphoma, one of the most common cancers in young adults.

Around 1,500 people are diagnosed each year in the UK with Hodgkin lymphoma, a type of cancer originating from white blood cells called lymphocytes.

One quarter to half of all cases of Hodgkin lymphoma are thought to be triggered by infection with Epstein-Barr virus (EBV)* however the disease can also develop in patients who have never been exposed to the virus. Scientists suspected inherited genes were involved in these cases, as having a family history of disease increases risk, but until now they have not been able to identify any specific genetic risk factors.

In a paper published, Professor Richard Houlston from the ICR and colleagues reveal three new variations in the letters of the DNA code that give an increased risk of developing Hodgkin lymphoma. Two of these genetic variants are more common in people not exposed to the virus.

“Many cases of Hodgkin lymphoma are linked to Epstein-Barr virus, but we have found the first evidence of genes that could be involved in promoting this cancer’s development in people not exposed to the virus,” Professor Houlston says. “Understanding the biological triggers for Hodgkin lymphoma is crucial as it opens the door to creating new targeted therapies for this disease.”

In the genome wide association study, funded by Leukaemia & Lymphoma Research and Cancer Research UK, the team scanned the whole genome of 589 Hodgkin lymphoma patients and compared the results to 5,199 people without the disease. They found the genetic variants on chromosomes 2, 8, and 10 were significantly more common among Hodgkin lymphoma sufferers than healthy controls, and then confirmed the results in a further 2,057 cases and 3,416 controls.

They also found the MHC region on chromosome 6 – which contains a family of genes involved in the immune system – is linked to a higher risk of disease, which has previously been suspected but not confirmed until now.

The other genetic variants identified are also located in or near genes thought to play an important role in the immune system: REL on chromosome 2, GATA3 on chromosome 10, and PVT1 on chromosome 8. Furthermore, the team found evidence that these genes may interact, and could therefore all be involved in the same disease-causing biological pathway.

Importantly, the changes to the DNA regions on chromosomes 2, 6, and 8 were significantly more common in patients who had not been exposed to Epstein-Barr virus, implying that genes in these regions are involved in another way of triggering disease independently of the virus. Further studies will be needed to work out exactly how this is occurring and pinpoint the precise genes that cause cancer.

Dr David Grant, Scientific Director at Leukaemia & Lymphoma Research, which co-funded the study, says, “More and more evidence is changing views on how Hodgkin lymphoma is caused. The link to EBV is still not clear after many years of research but this study will certainly throw new light on the genetic basis of this blood cancer. In the future new drugs can be developed to target these causes.”

Dr Lesley Walker, director of cancer information at Cancer Research UK, which co-funded the study, said, “Hodgkin’s lymphoma is one of the most curable forms of cancer, with around four out of five people now being successfully treated. We know that the EBV virus has a role to play in the development of Hodgkin’s lymphoma, but more than half of people with the disease show no signs of infection. This study takes us one step closer to fully understanding why the disease develops.”

* Epstein Barr virus is a very infectious type of herpes virus that can cause a number of diseases, ranging from mild cold-like symptoms to glandular fever and potentially other autoimmune disorders. In the US, about half of all 5-year-olds and up to 95% of adults have evidence of exposure.

Having a family member with Hodgkin lymphoma increases disease risk by between 3- and 9- fold; identical twins have a 99-fold increased risk. Most people who develop Hodgkin lymphoma are between 15 and 35 or over 55.